US6462036B1ExpiredUtility
Tricyclic pyrazole derivatives
Est. expiryNov 6, 2018(expired)· nominal 20-yr term from priority
Inventors:Kevin James DoylePaul RaffertyRobert W. SteeleDavid J. WilkinsLee D. ArnoldMichael HockleyAnna EricssonNobuhiko IwasakiNobuo Ogawa
A61P 37/08A61P 9/00A61P 7/04A61P 43/00A61P 35/00A61P 7/02A61P 31/04A61P 7/00A61P 9/10A61P 27/02A61P 27/06A61P 29/00A61P 19/00A61P 11/00A61P 19/02A61P 17/00A61P 17/06A61P 15/00A61P 17/02C07D 231/54C07D 491/04C07D 451/04C07D 409/04C07D 495/04C07D 403/10C07D 401/12C07D 403/12C07D 401/06C07D 401/04C07D 417/12C07D 409/14
85
PatentIndex Score
38
Cited by
20
References
55
Claims
Abstract
This invention relates to certain 3-aryl or 3-heteroaryl pyrazoles with 4,5(3,4)-bicyclic ring fusion which are inhibitors of protein kinase activity, of which some are novel compounds, to pharmaceutical compositions containing these pyrazoles and to processes for preparing these pyrazoles.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound represented by the formula:
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W, provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy: group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
2. A compound of claim 1 , wherein B is phenyl.
3. A compound of claim 2 , wherein R 1 is —Y—W, where Y is —CH 2 — and W is —NR 2 R 3 .
4. A compound of claim 3 , wherein ring A is unsubstituted.
5. A compound of claim 3 , wherein X is S or methylene.
6. A compound of claim 3 , wherein R 2 and R 3 , taken together with the nitrogen to which they are attached represent an optionally substituted heterocycloalkyl.
7. A compound of claim 6 , wherein the optionally substituted heterocycloalkyl formed by —NR 2 R 3 is selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
8. A compound of claim 7 , wherein the optionally substituted heterocycloalkyl formed by —NR 2 R 3 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
9. A compound of claim 3 , wherein R 2 is —H and R 3 is an optionally substituted heterocycloalkyl.
10. A compound of claim 9 , wherein R 3 is an optionally substituted heterocycloalkyl selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
11. A compound of claim 10 , wherein the optionally substituted heterocycloalkyl defined for R 3 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
12. A compound of claim 3 , wherein R 2 is —H and R 3 is an optionally substituted heterocycloalkylalkyl.
13. A compound of claim 12 , wherein the optionally substituted heterocycloalkylalkyl defined for R 3 has the heterocycloalkyl portion selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
14. A compound of claim 13 , wherein the heterocycloalkyl portion of R 3 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
15. A compound of claim 3 , wherein R 2 is —H and R 3 is a heteroaryl which is substitute with a —NR 9 (CH 2 ) 1-6 OR 4 , a —NR(CH 2 ) 1-6 CO 2 R 4 , a —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl.
16. A compound of claim 15 , wherein the heteroaryl defined for R 3 is selected from the group consisting of pyridyl, imidazolyl, furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl and benzo(b)thienyl.
17. A compound of claim 16 , wherein R 3 is pyridinyl.
18. A compound of claim 17 , wherein the pyridinyl is substituted with a 2-(N,N-dimethylamino)ethylamino.
19. A compound of claim 3 , wherein R 2 is —H and R 3 is a heteroaralkyl which is substituted with a —NR 9 (CH 2 ) 1-6 OR 4 , a —NR 9 (CH 2 ) 1-6 CO 2 R 4 , a —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl.
20. A compound of claim 19 , wherein the heteroaralkyl defined for R 3 has a heteroaryl which is selected from the group consisting of pyridyl, imidazolyl, furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl and benzo(b)thienyl.
21. A compound of claim 20 , wherein the heteroaryl portion of R 3 is pyridinyl.
22. A compound of claim 21 , wherein the pyridinyl is substituted with 2-(N,N-dimethylamino)ethylamino.
23. A compound of claim 2 , wherein ring A is substituted with —CH 2 NR 6 R 7 .
24. A compound of claim 23 , wherein m is 1 and R 1 is —H or —F.
25. A compound of claim 24 , wherein R 6 and R 7 , taken together with the nitrogen to which they are attached is an optionally substituted heterocycloalkyl.
26. A compound of claim 25 , wherein the heterocycloalkyl defined for —NR 6 R 7 is selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
27. A compound of claim 26 , wherein the heterocycloalkyl defined for —NR 6 R 7 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
28. A compound of claim 23 , wherein R 6 is —H and R 7 is an optionally substituted heterocycloalkyl.
29. A compound of claim 28 , wherein R 7 is selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
30. A compound of claim 29 , wherein R 7 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
31. A compound claim 23 , wherein R 6 is —H and R 7 is an optionally substituted heterocycloalkylalkyl.
32. A compound of claim 31 , wherein the heterocycloalkyl portion of R 7 is selected from the group consisting of a piperizine, a piperidine, homopiperazine, quinuclidine, azetidine, morpholine, thiomorpholine, pyrrolidine, thiazolidine, 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane.
33. A compound of claim 32 , wherein the heterocycloalkyl portion of R 7 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
34. A compound of claim 23 , wherein R 6 is —H and R 7 is an optionally substituted heteroaryl.
35. A compound of claim 34 , wherein R 7 is selected from the group consisting of pyridyl, imidazolyl, furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl and benzo(b)thienyl.
36. A compound of claim 35 , wherein R 7 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
37. A compound of claim 23 , wherein R 6 is —H and R 7 is an optionally substituted heteroaralkyl.
38. A compound of claim 37 , wherein the heteroaryl portion of R 7 is selected from the group consisting of pyridyl, imidazolyl, furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl and benzo(b)thienyl.
39. A compound of claim 20 , wherein the heteroaryl portion of R 7 is substituted with one or more substituents selected from the group consisting of a) a lower alkyl which is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; b) hydroxyl; c) —C(O) 2 R 4 ; d) —NR 4 R 5 , wherein R 4 and R 5 are each, independently, optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl or —C(O) 2 R 4 ; e) heterocycloalkyl which is optionally substituted with a lower alkyl, phenyl, heteroaryl, or heterocycloalkyl which is optionally substituted by a lower alkyl; f) —OR 4 , wherein R 4 is optionally substituted with a —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; g) —COR 4 , wherein R 4 is optionally substituted with —NR 4 R 5 , —OR 4 , heterocycloalkyl, or —C(O) 2 R 4 ; h) —NR 4 C(O) 2 R 5 ; and i) —NR 4 C(O)R 5 , wherein R 5 is optionally substituted with —OR 4 , —NR 4 R 5 , a heterocycloalkyl which is optionally substituted with a lower alkyl.
40. A compound of the following structural formula wherein X, R 2 and R 3 are selected from:
Entry
X
NR 2 R 3
1
CH 2
2
CH 2
3
CH 2
4
CH 2
5
CH 2
6
CH 2
7
CH 2
8
CH 2
9
CH 2
10
CH 2
11
CH 2
12
CH 2
13
CH 2
14
CH 2
15
S
16
S
17
S
18
S
19
S
20
S
21
S
22
S
23
S
24
S
25
S
26
S
27
S
28
S
29
S
30
S
31
S
32
S
33
S
34
S
35
S
36
S
37
S
38
S
39
CH 2
40
CH 2
41
CH 2
42
CH 2
43
CH 2
44
CH 2
45
CH 2
46
CH 2
NMe 2 (2HCl)
47
CH 2
48
CH 2
49
S
50
S
51
S
52
S
53
S
54
S
55
S
NMe 2
56
S
57
S
58
CO
59
CH 2
NH 2
60
CH 2
61
CH 2
62
CH 2
63
CH 2
64
CH 2
65
CH 2
66
CH 2
67
CH 2
68
CH 2
69
CH 2
70
CH 2
71
CH 2
72
S
73
S
74
S
75
S
76
S
77
S
78
S
79
CMe 2
NMe 2
80
CMe 2
81
SO 2
82
SO 2
83
S
84
CH 2
85
S
86
S
87
S
88
S
89
S
90
S
91
S
92
CH 2
93
CH 2
94
CH 2
95
CH 2
96
CH 2
97
CH 2
98
CH 2
99
CH 2
100
CH 2
101
CH 2
102
CH 2
103
CH 2
104
CH 2
105
S
106
S
107
S
108
S
109
S
110
S
111
S
tautomers thereof and the pharmaceutically acceptable salts thereof.
41. A compound of the following structural formula wherein B, R 6 and R 7 are selected from:
Entry
B with R 1
—NR 6 R 7
1
Ph
2
Ph
3
Ph
4
Ph
5
Ph
6
Ph
7
Ph
8
4-MeO—Ph
9
4-MeO—Ph
10
3-F—Ph
11
3-F—Ph
12
3-F—Ph
13
Et
14
Et
15
cyc-Pr
16
cyc-Pr
17
cyc-Pr
tautomers thereof and the pharmaceutically acceptable salts thereof.
42. A compound of the following formula wherein X, R 2 and R 3 are selected from:
Entry
X
NR 2 R 3
1
CH 2
2
CH 2
3
CH 2
NMe 2
4
CH 2
5
CH 2
6
S
7
S
NMe 2
8
S
9
S
10
S
11
S
tautomers thereof and the pharmaceutically acceptable salts thereof.
43. A compound of the following formula wherein R 6 , R 7 and R 8 are selected from:
Entry
R 8
NR 6 R 7
1
H
2
H
3
H
4
H
5
H
6
H
7
H
8
H
9
H
10
H
11
F
12
F
13
F
14
H
15
H
tautomers thereof and the pharmaceutically acceptable salts thereof.
44. A compound represented by the following structural formula:
tautomers thereof and the pharmaceutically acceptable salts thereof.
45. A method of inhibiting protein kinase activity in a mammal in need thereof comprising the step of administering to said mammal a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W; provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 R 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
46. A method of claim 45 , wherein R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; alkenyloxy; a C 2-4 alkenyl group optionally substituted with a C 1-6 alkyl group, a C 1-6 alkoxy group or a halo; a C 2-4 alkynyl group optionally substituted with a C 1-6 alkyl group, a C 1-6 alkoxy group or a halo; or a group represented by the formula —Y—W, provided that when R is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy or a halogen, ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy.
47. The method of claim 45 , wherein said protein kinase is a tyrosine kinase.
48. The method of claim 47 , wherein said tyrosine kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase.
49. The method of claim 48 , wherein said tyrosine kinase is selected from the group consisting of KDR, flt-1, TIE-2, Lck, Src, fyn and yes.
50. A method of affecting angiogenesis in a mammal in need thereof comprising the step of administering to said mammal a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W; provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
51. The method of claim 50 , wherein anti-angiogenic affect is effected.
52. A method of inhibiting the progression of a disease state in a mammal in need thereof wherein said disease is selected from the group consisting of cancer, arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collateral vascularization, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, retinopathy of prematurity, wound healing, ulcers, Helicobacter-caused diseases, fractures, endometriosis, diabetic retinopathy, cat scratch fever, and thyroid hyperplasia, burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, sepsis, adult respiratory distress syndrome, multiple-organ dysfunction syndrome, ascites and tumor-associated effusions and edema, comprising the step of administering a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W; provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
53. A method of inhibiting vascular hyperpermeability or the production of edema in a mammal in need thereof comprising the step of administering to said mammal a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W; provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl: group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
54. A method of inhibiting fertility or inducing abortifacient effects in a mammal in need thereof, comprising the step of administering to said mammal a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts arid the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W, provided that when R 1 is —H, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy, a halogen, or trifluoromethyl, then ring A is substituted with at least one substituent that is not a halo, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-6 alkoxy;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl, then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula —C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.
55. A method of inhibiting the progression of a disease state in a mammal in need thereof wherein said disease is selected from the group consisting of corneal disease, macular degeneration, endometriosis, thyroid hyperplasia, burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, sepsis, adult respiratory distress syndrome, and multiple-organ dysfunction syndrome, comprising the step of administering a compound of formula (I):
the racemic mixtures, racemic-diastereomeric mixtures, tautomers and optical isomers of said compounds and the pharmaceutically acceptable salts and the prodrugs thereof, wherein:
m is an integer from 1 to 10;
X represents a) an optionally substituted group of the formula —(CH 2 ) n — in which n is 1, 2 or 3, b) carbonyl, c) oxygen, d) a group of the formula —C═NOR 10 , in which R 10 is a C 1-4 alkyl group, e) a group of the formula NR 11 , in which R 11 is —H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, or f) a. group of formula S(O) p in which p is 0, 1 or 2;
B represents an alkyl, a cycloalkyl, an aryl, a pyridyl, a thienyl, a furyl or a pyrrolyl;
R 1 is —H; a halo; hydroxy; nitro; cyano; hydroxyamidino; aminomethyl; formamidomethyl; an optionally substituted alkenyloxy; an optionally substituted C 2-4 alkenyl; an optionally substituted C 2-4 alkynyl; or a group represented by the formula —Y—W;
Y is absent or a C 1-6 alkyl, C 1-6 alkoxy, —O—, —S— or —C(O)—;
W is —H, hydroxy, optionally substituted phenyl, C 1-6 alkoxy, or —NR 2 R 3 ;
provided that when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 are each, independently, a) —H; b) a substituted C 1-6 alkyl group, provided that the substituent is not —NR 6 R 7 ; c) an optionally substituted cycloalkyl; d) an optionally substituted heterocycloalkyl; e) an optionally substituted cycloalkylalkyl; f) an optionally substituted heterocycloalkylalkyl; g) a substituted heteroaryl or a substituted heteroaralkyl, provided that the heteroaryl or heteroaralkyl are substituted with —NR 9 (CH 2 ) 1-6 OR 4 , —NR 9 (CH 2 ) 1-6 CO 2 R 4 , —NR 9 (CH 2 ) 1-6 NR 4 R 5 , or an optionally substituted heterocycloalkyl; or
when B is phenyl and R 1 is —Y—W and W is —NR 2 R 3 , then R 2 and R 3 , together with the nitrogen atom to which they are attached, can represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
when B is not phenyl, then R 2 and R 3 are each, independently, —H, an optionally substituted C 1-6 alkyl group, —NH(CH 2 ) 1-6 NR 4 R 5 , an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or
when B is not phenyl, then R 2 and R 3 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 4 , R 5 and R 9 are for each occurrence, independently, —H or a C 1-6 alkyl; and
ring A is optionally substituted with one or more substituents selected from the group consisting of a) a halo; b) a C 1-6 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, and —NR 6 R 7 ; c) a C 1-6 alkoxy group optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, —NR 6 R 7 , an optionally substituted phenyl, and —NR 17 C(O)R 19 , provided that the substituents are not attached to the carbon which is attached to the oxygen of the alkoxy group; d) an optionally substituted phenoxy; e) hydroxy; f) a group of the formula C(O)R 12 in which R 12 is a hydroxy, a C 1-6 alkoxy or —NR 13 R 14 ; g) a group of the formula —NR 17 R 18 ; h) a group of the formula —NR 17 C(O)R 19 ; i) nitro; j) optionally substituted aralkyl; k) cyano; and l) a C 2-4 alkenyl group or a C 2-4 alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group and a halo;
R 6 and R 7 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 6 and R 7 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 13 and R 14 are each, independently, —H, an optionally substituted C 1-6 alkyl group, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or an optionally substituted heterocycloalkylalkyl; or
R 13 and R 14 together with the nitrogen atom to which they are attached represent an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;
R 17 and R 18 are each, independently, selected from the group consisting of —H, a C 1-12 alkyl group, a C 3-12 cycloalkyl group, and phenyl; and
R 19 is —H, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-12 cycloalkyl group, an optionally substituted phenyl or an optionally substituted aralkyl.Cited by (0)
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